Methods for treating neuropsychiatric disorders

ABSTRACT

The invention provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer&#39;s Disease, autism, depression, benign forgetfulness, childhood learning disorders, closed head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder a pharmaceutical composition containing (i) a therapeutically effective amount of D-alanine (or a modified form thereof), provided that the composition is substantially free of D-cycloserine, and/or (ii) D-serine (or a modified form thereof), and/or (iii) 105 to 500 mg of D-cycloserine (or a modified form thereof), and/or (iv) N-methylglycine (or a modified form thereof).

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of U.S. application Ser. No.10/196,686, filed Jul. 15, 2002, which is a continuation of U.S.application Ser. No. 09/834,351, filed Apr. 13, 2001, now U.S. Pat. No.6,420,351; which is a continuation of U.S. application Ser. No.09/291,296, filed Apr. 14, 1999, now U.S. Pat. No. 6,228,875; whichclaims the benefit of U.S. Provisional Application No. 60/081,645, filedApr. 14, 1998.

BACKGROUND OF THE INVENTION

[0002] Schizophrenia, Alzheimer's Disease, autism, depression, benignforgetfulness, childhood learning disorders, closed head injury, andattention deficit disorder are examples of neuropsychiatric disorders.Autism, for example, is a developmental mental disorder characterized byautistic behavior, social failure, and language delay. Alzheimer'sDisease is a form of dementia that typically involves progressive mentaldeterioration, manifested by memory loss, confusion, and disorientation.Alzheimer's Disease typically is treated by acetylcholine esteraseinhibitors such as tacrine hydrochloride or donepezil. Attention DeficitDisorder is a disorder that is most prevalent in children and isassociated with increased motor activity and a decreased attention span.Attention Deficit Disorder commonly is treated by administration ofpsychostimulants such as Ritalin or Dexedrin. Depression is a clinicalsyndrome that includes a persistent sad mood or loss of interest inactivities, which persists for at least two weeks in the absence oftreatment. Conventional therapeutics include serotonin uptake inhibitors(e.g., PROZAC), monoamine oxidase inhibitors, and tricyclicantidepressants.

[0003] The term schizophrenia represents a group of neuropsychiatricdisorders characterized by dysfunctions of the thinking process, such asdelusions, hallucinations, and extensive withdrawal of the patient'sinterests from other people. Approximately one percent of the worldwidepopulation is afflicted with schizophrenia, and this disorder isaccompanied by high morbidity and mortality rates.

[0004] Conventional antipsychotic drugs, which act on the dopamine D₂receptor, can be used to treat the positive symptoms of schizophrenia,such as delusion and hallucination. In general, conventionalantipsychotic drugs and the new atypical antipsychotic drugs, which acton the dopamine D₂ and 5HT₂ serotonin receptor, are limited in theirability to treat cognitive deficits and negative symptoms such as affectblunting (i.e., lack of facial expressions), anergia, and socialwithdrawal.

SUMMARY OF THE INVENTION

[0005] The invention derives from the discovery that neuropsychiatricdisorders characterized by a deficit in neurotransmission via the NMDAreceptor can be alleviated by a compound that acts as an agonist of theglycine site on the NMDA receptor or an inhibitor of glycine uptake. Thecompound is either a partial agonist such as D-cycloserine, which can beused at a dosage of 105-500 mg, or a full agonist (e.g., D-serine orD-alanine) that is selective for the NMDA receptor (compared to theinhibitory glycine receptor and other receptors), or a glycine uptakeinhibitor (e.g., N-methylglycine). The invention therefore provides newmethods for treating neuropsychiatric disorders in patients (i.e.,humans). Examples of disorders that can be treated by the methods of theinvention include schizophrenia, Alzheimer's Disease, autism,depression, benign forgetfulness, childhood learning disorders, closedhead injury, and attention deficit disorder. The methods entailadministering to a patient diagnosed as suffering from such aneuropsychiatric disorder a pharmaceutical composition that contains atherapeutically effective amount of an agonist of the glycine site ofthe NMDA receptor or a glycine uptake inhibitor, which agonist isrelatively selective for (a) the glycine site of the NMDA receptor,compared with (b) the inhibitory glycine receptor and other receptors.The pharmaceutical composition may include, for example, (i) atherapeutically effective amount of D-alanine (wherein thepharmaceutical composition is substantially free of D-cycloserine)and/or (ii) a therapeutically effective amount of D-serine, and/or (iii)D-cycloserine in an amount of 105-500 mg, and/or (iv) a therapeuticallyeffective amount of N-methylglycine.

[0006] In variations of the methods described herein, D-serine,D-alanine, D-cycloserine, and/or N-methylglycine can be substituted witha salt, ester, or alkylated form of the amino acid, or a precursor ofthe amino acid that is converted (e.g., metabolized) into the amino acidin vivo (e.g., D-phosphoserine, L-phosphoserine, or L-phosphoserine,N,N,N-trimethylglycine (betaine), or N,N-dimethylglycine).

[0007] Typically, a dosage of 100 μg to 100 g (e.g., 1 mg to 100 g; 1 mgto 100 mg; 10 mg to 100 g; 10 mg to 10 g; or 10 to 500 mg) is suitablefor D-alanine, D-serine, and N-methylglycine. D-cycloserine isadministered at a dosage of 105 to 500 mg. When the patient is treatedwith both D-serine and D-alanine, D-serine and D-alanine can beadministered to the patient simultaneously or sequentially, e.g., byformulating the D-serine and D-alanine as a single pharmaceuticalcomposition or as two or more pharmaceutical compositions. Likewise, thepatient can be treated with both D-serine and D-cycloserine, or D-serineand N-methylglycine, or D-alanine and N-methylglycine, or D-cycloserineand N-methylglycine simultaneously or sequentially. In one, but not theonly, suitable method of treatment, the pharmaceutical composition isadministered to the patient at least once daily for at least one week.If desired, the pharmaceutical composition can be administered to thepatient in more than one dose per day (e.g., 2, 3, or 4 doses).Generally, the patient is treated for at least one week; typically, thepatient is treated for at least several weeks (e.g., at least 4, 6, or 8weeks) or months (e.g., at least 4, 8, or 12 months). If necessary, thetreatment can continue indefinitely to keep the patient's symptoms undercontrol throughout his or her life.

[0008] If desired, a pharmaceutical composition containing D-alanine(substantially free of D-cycloserine), D-serine, D-cycloserine and/orN-methylglycine (or a modified version thereof, as described herein) canbe administered to a patient suffering from schizophrenia along with, orin sequence with, an art-known drug for treating schizophrenia (e.g.,olanzapine, clozapine, haloperidol, and the like). Similarly, D-alanine(typically substantially free of D-cycloserine), D-serine, D-cycloserineand/or N-methylglycine (or a modified version thereof, as describedherein) can be used in combination with, or in sequence with, otherart-known antipsychotics (e.g., “typical,” “atypical,” and depotantipsychotics for treating schizophrenia and other psychoticconditions), antidepressants (for treating depression), psychostimulants(for treating attention deficit disorder, depression, or learningdisorders), or Alzheimer's disease therapeutics (for treatingAlzheimer's disease). Such pharmaceutical compositions are includedwithin the invention. In general, the antipsychotic, antidepressant,psychostimulant, or Alzheimer's disease therapeutic typically isadministered at a dosage of 0.25-5000 mg/d (e.g., 5-1000 mg/d)).“Typical” antipsychotics are conventional antipsychotics such asphenothiazine, butryophenones, thioxantheses, dibenzoxazepines,dihydroindolones, and diphenylbutylpiperidines. “Atypical”antipsychotics are a new generation of antipsychotics which generallyact on the dopamine D₂ and 5HT₂ serotonin receptor and have high levelsof efficacy and a benign extrapyramidal symptom side effect profile.Examples of typical antipsychotics (and examples of suitable daily (d)dosages) include Chlorpromazine (5-2000 mg/d, e.g., 30-800 mg/d),Thioridazine (5-2000 mg/d, e.g., 20-800 mg/d), Mesoridazine (1-1000mg/d, e.g., 30-400 mg/d), Fluphenazine (0.5-200 mg/d, e.g., 1-40 mg/d),Perphenazine (0.5-300 mg/d, e.g., 10-65 mg/d), Trifluoperazine (0.5-200mg/d, e.g., 2-40 mg/d), Thiothixene (1-200 mg/d, e.g., 6-60 mg/d),Haloperidol (0.25-500 mg/d, e.g., 1-100 mg/d), Loxapine (1-1000 mg/de.g., 20-250 mg/d), Molindone (1-1000 mg/d, e.g., 15-225 mg/d),Acetophenazine (10-2000 mg/d, e.g., 30-500 mg/d), Chlorprothixene(5-2000 mg/d, e.g., 30-500 mg/d), Droperidol (0.25-500 mg/d, e.g., 1-100mg/d), Pimozide (0.25-500 mg/d, e.g., 1-100 mg/d). Examples of atypicalantipsychotics (and examples of suitable daily dosages) includeClozapine (5-2000 mg/d, e.g., 12-900 mg/d), Risperidone (0.25-500 mg/d,e.g., 2-16 mg/d), Olanzapine (1-100 mg/d, e.g., 5-10 mg/d), andQuetiapine (1-2000 mg/d, e.g., 50-750 mg/d). Depot antipsychotics alsocan be used, e.g., Haloperidol decanoate (10-1000 mg/month, e.g.,100-450 mg/month), Fluphenazine decanoate (5-1000 mg/month, e.g., 25-150mg/month), and Fluphenazine enanthate (5-1000 mg/month, e.g., 25-200mg/month). Additional antipsychotics include Butaperazine (0.5-500 mg/d,e.g., 1-200 mg/d), Carphenazine, (0.5-3000 mg/d, e.g., 1-1000 mg/d),Remoxipride (0.5-5000 mg/d, e.g., 1-2000 mg/d), Piperacetazine (0.5-500mg/d, e.g., 1-2000 mg/d), Sulpiride (0.5-5000 mg/d, e.g., 1-2000 mg/d),and Ziprasidone (0.5-500 mg/d, e.g., 1-200 mg/d). Examples ofantidepressants that can be used include Amitriptyline (5-1000 mg/d,e.g., 50-300 mg/d), Amoxapine (5-1000 mg/d, e.g., 50-600 mg/d),Bupropion (5-1000 mg/d, e.g., 200-450 mg/d), Bupropion SR (5-1000 mg/d,e.g., 150-400 mg/d), Clomipramine (5-1000 mg/d, e.g., 25-250 mg/d),Desipramine (5-1000 mg/d, e.g., 100-300 mg/d), Doxepin (5-1000 mg/d,e.g., 75-300 mg/d), Fluoxetine (1-200 mg/d, e.g., 20-80 mg/d),Fluvoxamine (5-1000 mg/d, e.g., 50-300 mg/d), Imipramine (5-1000 mg/d,e.g., 75-300 mg/d), Maprotiline (5-1000, e.g., 75-225 mg/d), Mirtazapine(1-200 mg/d, e.g., 15-45 mg/d), Nefazodone (5-1000 mg/d, e.g., 200-600mg/d), Nortriptyline (5-1000 mg/d, e.g., 75-150 mg/d), Paroxetine (1-200mg/d, e.g., 10-60 mg/d), Phenelzine (1-500 mg/d, e.g., 5-90 mg/d),Protriptyline (1-200 mg/d, e.g., 15-60 mg/d), Sertraline (5-1000 mg/d,e.g., 50-200 mg/d), Tranylcypromine (1-200 mg/d, e.g., 30-60 mg/d),Trazodone (5-1000 mg/d, e.g., 150-600 mg/d), Trimipramine (5-1000 mg/d,e.g., 5-300 mg/d), Venlafaxine (5-1000 mg/d, e.g., 75-375 mg/d), andVenlafaxine XR (5-1000 mg/d, e.g, 75-225 mg/d). Psychostimulants thatare particularly useful for treating attention deficit disorder includeDextroamphetamine (0.5-200 mg/d, e.g., 5-40 mg/d), Methamphetamine(0.5-200 mg/d, e.g., 5-25 mg/d), Methylphenidate (0.5-200 mg/d, e.g.,10-40 mg/d), and Pemoline (5-500 mg/d, e.g., 37.5-112.5 mg/d). Examplesof Alzheimer's disease therapeutics that can be used in the inventioninclude Donepezil (0.5-200 mg/d, e.g., 1-100 mg/d) and Tacrine (0.5-1000mg/d, e.g., 10-500 mg/d). Thus, the invention also providespharmaceutical compositions that contain D-alanine (typicallysubstantially free of D-cycloserine), D-serine, D-cycloserine and/orN-methylglycine (or a modified version thereof, as described herein)along with an antipsychotic, antidepressant, psychostimulant, orAlzheimer's disease therapeutic.

[0009] If desired, one can measure negative and/or positive and/orcognitive symptom(s) of schizophrenia before and after treatment of thepatient. A reduction in such a symptom indicates that the patient'scondition has improved. Improvement in the symptoms of schizophrenia canbe assessed using the Scales for the Assessment of Negative Symptoms(SANS) or Positive and Negative Syndrome Scale (PANSS) (see, e.g.,Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SANS),Iowa City, Iowa and Kay et al., 1987, Schizophrenia Bulletin13:261-276). Likewise, one can measure improvement of otherneuropsychiatric disorders in patients who have been treated by themethods of the invention.

[0010] As used herein, the term “neuropsychiatric disorder” refers to adisease having a pathophysiological component of attenuated NMDAreceptor-mediated neurotransmission. Examples of such disorders includeschizophrenia, Alzheimer's disease, autism, depression, benignforgetfulness, childhood learning disorders, closed head injury, andattention deficit disorder.

[0011] As used herein, the term “schizophrenia” refers to a psychiatricdisorder that includes at least two of the following: delusions,hallucinations, disorganized speech, grossly disorganized or catatonicbehavior, or negative symptoms. Patients can be diagnosed asschizophrenic using the DSM-IV criteria (APA, 1994, Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition), Washington,D.C.).

[0012] The term “Alzheimer's Disease” refers to a progressive mentaldeterioration manifested by memory loss, confusion and disorientationbeginning in late middle life and typically resulting in death in fiveto ten years. Pathologically, Alzheimer's Disease can be characterizedby thickening, conglutination, and distortion of the intracellularneurofibrils, neurofibrillary tangles and senile plaques composed ofgranular or filamentous argentophilic masses with an amyloid core.Methods for diagnosing Alzheimer's Disease are known in the art. Forexample, the National Institute of Neurological and CommunicativeDisorders and Stroke-Alzheimer's Disease-and the Alzheimer's Disease andRelated Disorders Association (NINCDS-ADRDA) criteria can be used todiagnose Alzheimer's Disease (McKhann et al., 1984, Neurology34:939-944). The patient's cognitive function can be assessed by theAlzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; Rosenet al., 1984, Am. J. Psychiatry 141:1356-1364).

[0013] As used herein, the term “autism” refers to a state of mentalintroversion characterized by morbid self-absorption, social failure,language delay, and stereotyped behavior. Patients can be diagnosed assuffering from autism by using the DSM-IV criteria.

[0014] As used herein, the term “depression” refers to a clinicalsyndrome that includes a persistent sad mood or loss of interest inactivities, which lasts for at least two weeks in the absence oftreatment. The DSM-IV criteria can be used to diagnose patients assuffering from depression.

[0015] The term “benign forgetfulness,” as used herein, refers to a mildtendency to be unable to retrieve or recall information that was onceregistered, learned, and stored in memory (e.g., an inability toremember where one placed one's keys or parked one's car). Benignforgetfulness typically affects individuals after 40 years of age andcan be recognized by standard assessment instruments such as theWechsler Memory Scale (Russell, 1975, J. Consult Clin. Psychol.43:800-809).

[0016] As used herein, the term “childhood learning disorders” refers toan impaired ability to learn, as experienced by certain children. Suchlearning disorders can be diagnosed by using the DSM-IV criteria.

[0017] The term “closed head injury,” as used herein, refers to aclinical condition after head injury or trauma which condition can becharacterized by cognitive and memory impairment. Such a condition canbe diagnosed as “amnestic disorder due to a general medical condition”according to DSM-IV.

[0018] The term “attention deficit disorder,” as used herein, refers toa disorder that is most commonly exhibited by children and which can becharacterized by increased motor activity and a decreased attentionspan. The DSM-IV criteria can be used to diagnose attention deficitdisorder.

[0019] The terms “D-serine” and “D-alanine” refer to the D isomers ofthe amino acids serine and alanine, respectively. As D isomers, ratherthan L isomers, these amino acids are not naturally found in proteins.

[0020] “Negative” symptoms of schizophrenia include affect blunting,anergia, alogia and social withdrawal, which can be measured using SANS(the Scales for the Assessment of Negative Symptoms; see Andreasen,1983, Scales for the Assessment of Negative Symptoms (SANS), Iowa City,Iowa).

[0021] “Positive” symptoms of schizophrenia include delusion andhallucination, which can be measured using PANSS (the Positive andNegative Syndrome Scale; see Kay et al., 1987, Schizophrenia Bulletin13:261-276).

[0022] “Cognitive” symptoms of schizophrenia include impairment inobtaining, organizing, and using intellectual knowledge which can bemeasured by the Positive and Negative Syndrome Scale-cognitive subscale(PANSS-cognitive subscale)(Lindenmayer et al., 1994, J. Nerv. Ment. Dis.182:631-638) or with cognitive tasks such as the Wisconsin Card SortingTest.

[0023] A “full” agonist of the NMDA receptor is a compound that producesa maximal response at full receptor occupancy.

[0024] A “partial” agonist of the NMDA receptor is a compound thatproduces a lower maximal response at full receptor occupancy than dofull agonists.

[0025] A “glycine uptake inhibitor of the NMDA receptor” is a compoundthat inhibits the re-uptake of glycine and increases the availability ofglycine for the NMDA receptor (e.g., N-methylglycine).

[0026] The invention offers several advantages over many art-knownmethods for treating neuropsychiatric disorders. For example, unlikemany conventional antipsychotic therapeutics, D-serine, D-alanine, andN-methylglycine can produce a desirable reduction in the positive,negative, and cognitive symptoms of schizophrenia. As shown by theexamples set forth below, clinically significant improvement can beachieved even with patients who are poorly responsive to treatment byconventional antipsychotics. In addition, no significant side effectswere detected after treatment of schizophrenia patients with D-serine,D-alanine, or N-methylglycine. In contrast, conventional antipsychoticstypically lead to tardive dyskinesia (irreversible, involuntary movementdisorder), extrapyramidal symptoms, and akathesia symptoms.

[0027] Other features and advantages of the invention will be apparentfrom the following detailed description, and from the claims.

DETAILED DESCRIPTION

[0028] The invention provides methods for treating a patient diagnosedas suffering from a neuropsychiatric disorder having a deficit inneurotransmission via the NMDA receptor (e.g., schizophrenia,Alzheimer's Disease, autism, depression, benign forgetfulness, childhoodlearning disorders, closed head injury, and attention deficit disorder).As described above, a variety of methods for diagnosing these disordersare known to those of skill in the art of clinical psychiatry, and anyconventional diagnostic method can be used in conjunction with theinvention.

[0029] The treatment method of the invention entails administering to apatient diagnosed as having a neuropsychiatric disorder a pharmaceuticalcomposition containing a therapeutically effective amount of (i) anagonist of the glycine site of the NMDA receptor, which agonist isrelatively selective for (a) the glycine site of the NMDA receptor,compared with (b) an inhibitory glycine receptor or any other receptor,or (ii) a glycine uptake inhibitor. For example, suitable pharmaceuticalcompositions may include (i) D-alanine substantially free ofD-cycloserine and/or (ii) D-serine and/or (iii) N-methylglycine.D-serine and D-alanine are commercially available (e.g., from SpectrumQuality Products, Inc., Gardena, Calif.). Where D-alanine is used, thepharmaceutical composition is “substantially free” of D-cycloserine,meaning that the composition lacks D-cycloserine, or D-cycloserine isnot included at a level sufficient to have a statistically significanteffect upon the efficacy of the pharmaceutical composition, asdetermined by any method (e.g., by comparing PANSS and/or SANS scoresbefore and after treatment of the patient). In general, this means thatD-cycloserine is absent from the pharmaceutical composition or presentin an amount such that the patient receives less than 0.02 mg/day.

[0030] Treatment includes administering a therapeutically effectiveamount of a composition containing D-alanine (substantially free ofD-cycloserine) and/or D-serine and/or N-methylglycine to a patient inneed of such treatment, thereby treating the neuropsychiatric disorder.Such compositions typically contain from about 0.1 to 90% by weight(such as 1 to 20% or 1 to 10%) of D-alanine, D-serine, orN-methylglycine in a pharmaceutically acceptable carrier. Regardless ofthe concentration of D-serine or D-alanine in the pharmaceuticalcomposition, D-serine and/or D-alanine and/or N-methylglycine isadministered to the patient at a dosage of 10 mg to 100 g. Moretypically, D-serine and/or D-alanine and/or N-methylglycine isadministered at a dosage of 100 mg to 10 g. Generally, treatmentcontinues for at least several weeks to several years or life-long asneeded.

[0031] In an alternative method for treating a neuropsychiatric disorderin a patient, a pharmaceutical composition containing D-cycloserine inan amount equivalent to a dosage of 105 to 500 mg/day is administered toa patient in need of such treatment. For example, the dosage can be inan amount of 125 to 400 mg, such as 150 to 300 mg (e.g., 175 mg, 200 mg,225 mg, or 250 mg). D-cycloserine (D-4-amino-3-isoxazolidinone) iscommercially available from Eli Lilly, Inc. (Indianapolis, Ind.).Generally, treatment continues for at least one week and can continuefor several years or life-long as needed to control the patient'ssymptoms.

[0032] In all of the methods of the invention, D-alanine, D-serine,and/or D-cycloserine and/or N-methylglycine can be substituted with amodified version of the amino acid, such as a salt, ester, alkylatedform, or a precursor of the amino acid. For example, the amino acid canbe in the form of a sodium salt, potassium salt, calcium salt, magnesiumsalt, zinc salt, or ammonium salt. Such salt forms of D-serine,D-alanine, N-methylglycine and D-cycloserine can be made in accordancewith conventional methods (see, e.g., Organic Chemistry, pgs. 822-823,Morrison and Boyd, ed., Fifth Edition, Allyn and Bacon, Inc., Newton,Mass.). Other modified forms of D-serine, D-alanine, N-methylglycine andD-cycloserine also can be used in the methods of the invention. Forexample, the carboxy group of the amino acid can be converted to anester group by reaction with an alcohol in accordance with standardesterification methods (Id. at 841-843). For example, alcohols having1-20 carbon atoms can be used to produce an ester of D-serine,D-alanine, N-methylglycine or D-cycloserine for use in the invention(e.g., methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-,sec-butyl-, tert-butyl-, pentyl-, isopentyl-, tert-pentyl-, hexyl-,heptyl-, octyl-, decyl-, dodecyl-, tetradecyl-, hexadecyl-, octadecyl-,and phenyl-alcohols can be used). In another variation, the amino groupof the amino acid can be alkylated, using conventional methods, toproduce a secondary or tertiary amino group by ammonolysis of halides orreductive amination (Id. at 939-948). For example, an alkyl group having1-20 carbon atoms can be added to the amino acid to produce an alkylatedamino acid (e.g., methyl-, ethyl-, propyl-, isopropyl-, butyl-,isobutyl-, sec-butyl-, tert-butyl-, pentyl-, isopentyl-, tert-pentyl-,hexyl-, heptyl-, octyl-, decyl-, dodecyl-, tetradecyl-, hexadecyl-,octadecyl- and phenyl-groups can be added to the amino acid).D-phosphoserine and L-phosphoserine are examples of precursors ofD-serine, and are commercially available (e.g., from Sigma Chemical, St.Louis, Mo.). N,N,N-trimethylglycine (betaine) and N,N-dimethylglycineare examples of precursors of N-methylglycine.

[0033] In all of the methods of the invention, appropriate dosages ofD-alanine, D-serine, D-cycloserine, or N-methylglycine (or modifiedversions thereof) can readily be determined by those of ordinary skillin the art of medicine by monitoring the patient for signs of diseaseamelioration or inhibition, and increasing or decreasing the dosageand/or frequency of treatment as desired.

[0034] The pharmaceutical compositions can be administered to thepatient by any, or a combination, of several routes, such as oral,intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary,transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal,intramuscular, or long term depot preparation. Solid compositions fororal administration can contain suitable carriers or excipients, such ascorn starch, gelatin, lactose, acacia, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate,sodium chloride, lipids, alginic acid, or ingredients for controlledslow release. Disintegrators that can be used include, withoutlimitation, micro-crystalline cellulose, corn starch, sodium starchglycolate and alginic acid. Tablet binders that may be used include,without limitation, acacia, methylcellulose, sodiumcarboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch, and ethylcellulose.

[0035] Liquid compositions for oral administration prepared in water orother aqueous vehicles can include solutions, emulsions, syrups, andelixirs containing, together with the active compound(s), wettingagents, sweeteners, coloring agents, and flavoring agents. Variousliquid and powder compositions can be prepared by conventional methodsfor inhalation into the lungs of the patient to be treated.

[0036] Injectable compositions may contain various carriers such asvegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate,ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol,propylene glycol, liquid polyethylene glycol, and the like). Forintravenous injections, the compounds may be administered by the dripmethod, whereby a pharmaceutical composition containing the activecompound(s) and a physiologically acceptable excipient is infused.Physiologically acceptable excipients may include, for example, 5%dextrose, 0.9% saline, Ringer's solution or other suitable excipients.For intramuscular preparations, a sterile composition of a suitablesoluble salt form of the compound can be dissolved and administered in apharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5%glucose solution, or depot forms of the compounds (e.g., decanoate,palmitate, undecylenic, enanthate) can be dissolved in sesame oil.Alternatively, the pharmaceutical composition can be formulated as achewing gum, lollipop, or the like.

EXAMPLES

[0037] The following examples demonstrate that D-alanine, D-serine, andN-methylglycine each can be used to treat a neuropsychiatric disorder inpatients.

[0038] Patients

[0039] This study employed 37 patients who were diagnosed as havingschizophrenia. All patients fulfilled the DSM-IV diagnosis ofschizophrenia (APA, 1994, Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Washington, D.C.). All of the patients alsofulfilled the criteria of primary deficit syndrome, with a SANS score ofmore than 40 (Kirkpatrick et al., 1989, Psychiatry Research 30:119-123;Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SANS),Iowa City, Iowa). All of the patients were poorly responsive totreatment by other antipsychotic drugs, and had been kept on a stabledose of an antipsychotic drug for at least 3 months prior to enrollmentin this study.

[0040] Assessments

[0041] Several scales were used to assess the severity of the disorderin each patient. At the beginning of the study (i.e., the baseline), thePANSS, SANS, and Global Assessment Scales (CGI) were used. Each scalealso was completed at the end of each 2-week period throughout thestudy. These assessments were performed by a psychiatrist who was blindto the treatment assignment. The Wisconsin Card Sort Test was used toprovide a cognitive rating of the patients; in general, schizophrenicpatients perform poorly on this test. The Wisconsin Card Sort Test wasadministered only at the initiation of the study and at the end of the6-week study. To measure side effects, the Simpson-Angus Scale was usedto measure extrapyramidal symptoms (EPS; Simpson et al., 1970, ActaPsychiatrica Scandinavia Suppl. 212:11-19). The Abnormal InvoluntaryMovement Scale (AIMS) was used to measure dyskinesia (Simpson et al.,1970, Acta Psychiatrica Scandinavia Suppl. 212:11-19). The Barnes Scalewas used to measure akathesia (Barnes, 1989, Brit. J. Psychiatry154:672-676). The side effects of D-serine, D-alanine, andN-methylglycine treatments were assessed biweekly according to the UKUside effects rating scale (Scandinavian Society of PsychopharmacologyCommittee of Clinical Investigation: The UKU side effect rating scale:scale for the registration of unwanted effects of psychotropics. Acta.Psychiatr. Scand. 1987; Suppl. 334:81-94).

[0042] Treatment and Results

[0043] Using double-blind conditions, the patients were randomlyassigned to receive placebo (fruit juice), D-serine (30 mg/kg/day),D-alanine (60-100 mg/kg/day), or N-methylglycine (30 mg/kg/day) once aday by mouth for a period of 6 weeks. As indicated by the results shownin Table 1, treatment with D-serine, D-alanine, or N-methylglycineimproved the schizophrenic symptoms and cognitive deficit of thepatients. More specifically, treatment with D-serine resulted in a 21%reduction of the negative symptoms (on the SANS scale), and it resultedin a 17% reduction of the positive symptoms (on the PANSS-positivesubscale). Treatment with D-alanine resulted in an 11% reduction of thenegative symptoms and a 12% reduction of the positive symptoms.Treatment with N-methylglycine resulted in a 20% reduction of thenegative symptoms and a 15% reduction of the positive symptoms. Thesereductions in the negative and positive symptoms represented clinicallysignificant improvement. Treatment with each of D-serine, D-alanine, andN-methylglycine also improved cognition, as measured using thePANSS-cognitive subscale and the Wisconsin Card Sort Test. These resultsindicate that D-serine, D-alanine, and N-methylglycine are effective intreating schizophrenia even in patients who are poorly responsive totreatment by conventional antipsychotic drugs.

[0044] Using the UKU scale for rating side effects, no side effects werenoted after treatment with D-serine, D-alanine, or N-methylglycine. Inaddition, there was no newly emergent tardive dyskinesia or worsening ofextrapyramidal or akathesia symptoms. Thus, D-serine, D-alanine, andN-methylglycine offer an advantage over many conventional drugs fortreating schizophrenia in that they do not cause significant sideeffects. TABLE 1 Effects of D-serine, D-alanine, and N-methylglycineTreatment on Schizophrenia Patients D-serine D-alanine N-methylglycinePlacebo Clinical Symptoms Negative −21%*  −12%*  −20%*   −1% SymptomsPositive −17%*  −11%*  −15%*     3% Symptoms CGI 4.8->2.6* 3.9->2.8*4.2->2.7* 4.5->4.0 Cognition Cognitive −12%*  −11%*  −12%*     1%symptoms WCST +0.9 (category)* +0.5* +0.7* −0.5 Side Effects EPS1.4-->1.7 3.1-->3.1 2.1-->2.1 3.3-->3.4 AIMS 0.3-->0.3 0.5-->0.10.4-->0.3 0.5-->0.9 Barnes 0.4-->0.8 0.4-->0.6 0.5-->0.6 0.9-->0.9

OTHER EMBODIMENTS

[0045] It is to be understood that, while the invention has beendescribed in conjunction with the detailed description thereof, theforegoing description is intended to illustrate and not limit the scopeof the invention, which is defined by the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method for treating Alzheimer's disease, themethod comprising administering to a patient suffering from Alzheimer'sdisease a therapeutic agent selected from the group consisting ofD-cycloserine and a salt of D-cycloserine, wherein the amount of thetherapeutic agent is equivalent to 105-500 mg of D-cycloserine per day,and wherein the therapeutic agent is administered to the patient for atleast four weeks.
 2. The method of claim 1, wherein the therapeuticagent is selected from the group consisting of a sodium salt, apotassium salt, a calcium salt, a magnesium salt, a zinc salt, and anammonium salt of D-cycloserine.
 3. The method of claim 1, wherein theD-cycloserine or salt of D-cycloserine is administered in a doseequivalent to 125-400 mg of D-cycloserine per day.
 4. The method ofclaim 1, wherein the D-cycloserine or salt of D-cycloserine isadministered in a dose equivalent to 150-300 mg of D-cycloserine perday.
 5. The method of claim 1, wherein the composition is administeredorally, intravenously, trans-mucosally, transdermally, ocularly,buccally, sublingually, intraperitoneally, intrathecally,intramuscularly, by a pulmonary route, or by depot preparation.
 6. Themethod of claim 1, wherein the therapeutic agent is D-cycloserine and isadministered for at least 6 weeks.
 7. The method of claim 1, wherein thetherapeutic agent is D-cycloserine and is administered for at least 8weeks.
 8. The method of claim 1, wherein the therapeutic agent isD-cycloserine and is administered for at least 4 months.
 9. The methodof claim 1, wherein the therapeutic agent is D-cycloserine and isadministered for at least 8 months.
 10. The method of claim 1, whereinthe therapeutic agent is D-cycloserine and is administered for at least12 months.
 11. A method for treating Alzheimer's disease, the methodcomprising administering to a patient suffering from Alzheimer's diseasea therapeutic agent selected from the group consisting of an ester ofD-cycloserine, a precursor of D-cycloserine, and alkylatedD-cycloserine, wherein the amount of the therapeutic agent is equivalentto 105-500 mg of D-cycloserine per day, and wherein the therapeuticagent is administered to the patient for at least four weeks.
 12. Themethod of claim 11, wherein the therapeutic agent is an ester ofD-cycloserine.
 13. The method of claim 11, wherein the therapeutic agentis a precursor of D-cycloserine.
 14. The method of claim 11, wherein thetherapeutic agent is an alkylated D-cycloserine.
 15. The method of claim11, wherein the composition is administered orally, intravenously,trans-mucosally, transdermally, ocularly, buccally, sublingually,intraperitoneally, intrathecally, intramuscularly, by a pulmonary route,or by depot preparation.
 16. The method of claim 11, wherein thetherapeutic agent is administered for at least 6 weeks.
 17. The methodof claim 11, wherein the therapeutic agent is administered for at least8 weeks.
 18. The method of claim 11, wherein the therapeutic agent isadministered for at least 4 months.
 19. The method of claim 11, whereinthe therapeutic agent is administered for at least 8 months.
 20. Themethod of claim 11, wherein the therapeutic agent is administered for atleast 12 months.
 21. A method for treating Alzheimer's disease, themethod comprising administering to a patient suffering from Alzheimer'sdisease (i) a therapeutically effective amount of a therapeutic agentselected from the group consisting of D-cycloserine and a salt ofD-cycloserine; and (ii) an acetylcholine esterase inhibitor.
 22. Themethod of claim 21, wherein the therapeutic agent is D-cycloserine. 23.The method of claim 21, wherein the therapeutic agent is selected fromthe group consisting of a sodium salt, a potassium salt, a calcium salt,a magnesium salt, a zinc salt, and an ammonium salt of D-cycloserine.24. The method of claim 21, wherein the acetylcholine esterase inhibitoris Donepezil or Tacrine.
 25. The method of claim 21, wherein the amountof the therapeutic agent is equivalent to105-500 mg of D-cycloserine.26. The method of claim 25, wherein the amount of the therapeutic agentis equivalent to 125-400 mg of D-cycloserine per day.
 27. The method ofclaim 26, wherein the amount of the therapeutic agent is equivalent to150-300 mg of D-cycloserine per day.
 28. The method of claim 21, whereinthe therapeutic agent and the acetylcholine esterase inhibitor areadministered orally, intravenously, trans-mucosally, transdermally,ocularly, buccally, sublingually, intraperitoneally, intrathecally,intramuscularly, by a pulmonary route, or by depot preparation.
 29. Amethod for treating Alzheimer's disease, the method comprisingadministering to a patient suffering from Alzheimer's disease (i) atherapeutically effective amount of a therapeutic agent selected fromthe group consisting of an ester of D-cycloserine, a precursor ofD-cycloserine, and alkylated D-cycloserine; and (ii) an acetylcholineesterase inhibitor.
 30. The method of claim 29, wherein the therapeuticagent is an ester of D-cycloserine having an ester group with 1-20carbon atoms.
 31. The method of claim 29, wherein the therapeutic agentis an alkylated D-cycloserine having an alkyl group with 1-20 carbonatoms.
 32. The method of claim 29, wherein the therapeutic agent is aprecursor of D-cycloserine.
 33. The method of claim 29, wherein theacetylcholine esterase inhibitor is Donepezil or Tacrine.
 34. The methodof claim 29, wherein the amount of the therapeutic agent is equivalentto 105-500 mg of D-cycloserine.
 35. The method of claim 34, wherein theamount of the therapeutic agent is equivalent to 125-400 mg ofD-cycloserine per day.
 36. The method of claim 35, wherein the amount ofthe therapeutic agent is equivalent to 150-300 mg of D-cycloserine perday.
 37. The method of claim 29, wherein the therapeutic agents and theacetylcholine esterase inhibitor are administered orally, intravenously,trans-mucosally, transdermally, ocularly, buccally, sublingually,intraperitoneally, intrathecally, intramuscularly, by a pulmonary route,or by depot preparation.
 38. A method for treating Alzheimer's disease,the method comprising administering to a patient diagnosed as sufferingfrom Alzheimer's disease (i) a first therapeutic agent selected from thegroup consisting of D-cycloserine and a salt of D-cycloserine; and (ii)a second therapeutic agent selected from the group consisting ofantipsychotics, antidepressants, psychostimulants, and Alzheimer'sdisease therapeutics; wherein the therapeutic agent is equivalent to105-500 mg of D-cycloserine.
 39. A method for treating Alzheimer'sdisease, the method comprising administering to a patient diagnosed assuffering from Alzheimer's disease (i) a first therapeutic agentselected from the group consisting of an ester of D-cycloserine, aprecursor of D-cycloserine, and alkylated D-cycloserine; and (ii) asecond therapeutic agent selected from the group consisting ofantipsychotics, antidepressants, psychostimulants, and Alzheimer'sdisease therapeutics; wherein the first therapeutic agent is in anamount equivalent to 105-500 mg of D-cycloserine.
 40. A pharmaceuticalcomposition comprising: (i) a therapeutically effective amount of atherapeutic agent selected from the group consisting of D-cycloserineand a salt of D-cycloserine; and (ii) an acetylcholine esteraseinhibitor.
 41. The method of claim 40, wherein the therapeutic agent isequivalent to 105-500 mg of D-cycloserine.
 42. The composition of claim40, wherein the therapeutic agent is selected from the group consistingof a sodium salt, a potassium salt, a calcium salt, a magnesium salt, azinc salt, and an ammonium salt of D-cycloserine.
 43. The composition ofclaim 40, wherein acetylcholine esterase inhibitor is Donepezil orTacrine.
 44. A pharmaceutical composition comprising: (i) atherapeutically effective amount of a therapeutic agent selected fromthe group consisting of an ester of D-cycloserine, a precursor ofD-cycloserine, and alkylated D-cycloserine; and (ii) an acetylcholineesterase inhibitor.
 45. The method of claim 44, wherein the amount ofthe therapeutic agent is equivalent to 105-500 mg of D-cycloserine. 46.The composition of claim 44, wherein the acetylcholine esteraseinhibitor is Donepezil or Tacrine.
 47. A pharmaceutical compositioncomprising: (i) a first therapeutic agent selected from the groupconsisting of D-cycloserine and a salt of D-cycloserine; and (ii) asecond therapeutic agent selected from the group consisting ofantipsychotics, antidepressants, psychostimulants, and Alzheimer'sdisease therapeutics; wherein the therapeutic agent is in an amountequivalent to 105-500 mg of D-cycloserine.
 48. A pharmaceuticalcomposition comprising: (i) a first therapeutic agent selected from thegroup consisting of an ester of D-cycloserine, a precursor ofD-cycloserine, and alkylated D-cycloserine; and (ii) a secondtherapeutic agent selected from the group consisting of antipsychotics,antidepressants, psychostimulants, and Alzheimer's disease therapeutics;wherein the therapeutic agent is in an amount equivalent to 105-500 mgof D-cycloserine.